Elucidation of the mechanism of regulatory T cell differentiation in the tumor microenvironment

• Project/Area Number: 21K15542
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Itahashi Kota 国立研究開発法人国立がん研究センター, 先端医療開発センター, 研究員 (10828990)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 腫瘍免疫 / 制御性T細胞 / エピゲノム

Outline of Research at the Start

ヒトの腫瘍局所には制御性T細胞が多く浸潤し、腫瘍に対する免疫応答を抑制し、予後不良因子として知られている。我々の研究室では、腫瘍中のPD-1陽性制御性T細胞が、PD1阻害薬投与によって活性化して有効な抗腫瘍免疫を抑制し、PD-1阻害薬の耐性機序や急性増悪の原因になることを明らかにした。臨床上で腫瘍浸潤制御性T細胞の重要性が明らかになった一方で、腫瘍局所で制御性T細胞が活性化表現型に分化する機序やPD-1蛋白の発現が誘導される機構に関しては不明な点が多い。申請者は特にエピゲノムの改変の観点からこれらの疑問点を明らかにしていき、将来的な免疫療法の耐性機序の解明や新規の免疫療法の開発に繋げていく。

Outline of Final Research Achievements

Regulatory T (Treg) cells are required for maintaining self-tolerance and preventing the development of autoimmune diseases. However, in tumor immunity, Treg cells abundantly infiltrate the tumor microenvironment (TME) and promote tumor progression by suppressing effective anti-tumor immune responses. Although the differentiation process of CD8+ T cells toward the exhausted state in the TME has been well investigated, Treg cell differentiation in the TME is still an active area of investigation. Multi-omics analysis of lung tumor-infiltrating Treg cells have clarified the chromatin landscape and the core network of transcription factors that contribute to the differentiation process of human Treg cells in the TME.

Academic Significance and Societal Importance of the Research Achievements

血液、正常組織、がん組織内の制御性T細胞を詳細に解析して得られた結果は、がん組織内の制御性T細胞を標的とする免疫治療開発のみならず、制御性T細胞が発症に関わる自己免疫性疾患の理解などを始めとして、様々な医学研究に応用されることが期待される。

Research Products

• [Journal Article] BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors (2022)
  • Author(s): Itahashi Kota、Irie Takuma、Yuda Junichiro、Kumagai Shogo、Tanegashima Tokiyoshi、Lin Yi-Tzu、Watanabe Sho、Goto Yasushi、Suzuki Jun、Aokage Keiju、Tsuboi Masahiro、Minami Yosuke、Ishii Genichiro、Ohe Yuichiro、Ise Wataru、Kurosaki Tomohiro、Suzuki Yutaka、Koyama Shohei、Nishikawa Hiroyoshi
  • Journal Title: Science Immunology Volume: 7 Issue: 76 Pages: 1-20
  • DOI: 10.1126/sciimmunol.abk0957
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulatory T‐cell development in the tumor microenvironment (2022)
  • Author(s): Itahashi Kota、Irie Takuma、Nishikawa Hiroyoshi
  • Journal Title: European Journal of Immunology Volume: 52 Issue: 8 Pages: 1216-1227
  • DOI: 10.1002/eji.202149358
  • Peer Reviewed / Open Access